The incidence of epilepsy is highest in the first year of life with a reported incidence around 1.8-3.5/1,000 live births in the United States. Silverstein et al., “Neonatal seizures” Annals Of Neurology 62:112-120 (2007); and Jensen F., “Neonatal seizures: An update on mechanisms and management” Clinics In Perinatology 36:881-900 (2009). Although many antiepileptic drugs (AEDs) have been developed over the past several decades, neonatal seizures are often refractory to current AEDs, which are more effective in older children or adults. Painter et al., “Phenobarbital compared with phenytoin for the treatment of neonatal seizures” The New England Journal Of Medicine 341:485-489 (1999); van Rooij et al., “Treatment of neonatal seizures” Seminars In Fetal & Neonatal Medicine 18:209-215 (2013); and Dzhala et al., “NKCC1 transporter facilitates seizures in the developing brain” Nature Medicine 11:1205-1213 (2005).
In some cases, even after AED application, electroencephalographic (EEG) recordings show ongoing cortical epileptic activity in neonates, which may impair cognitive development and later result in epilepsy. Connell et al., “Clinical and EEG response to anticonvulsants in neonatal seizures” Archives Of Disease In Childhood 64:459-464 (1989); Glykys et al., “Differences in cortical versus subcortical GABAergic signaling: a candidate mechanism of electroclinical uncoupling of neonatal seizures” Neuron 63:657-672 (2009); and Puskarjov et al., “Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures” Epilepsia 55:806-818 (2014).
Epileptic seizures are often caused by overexcitation of the brain circuits, which can be inhibited by boosting GABAA receptors (GABAA-Rs), the major inhibitory receptors in the adult brain. Accordingly, AEDs are often developed to increase GABAA-R function, such as benzodiazepine and barbiturate drugs. Bialer, M. & White, H. S. Key factors in the discovery and development of new antiepileptic drugs. Nature reviews. Drug discovery 9, 68-82 (2010). However, while GABAA-Rs are mostly inhibitory in the adult brain, they are excitatory in the developing brain. Chen, G., Trombley, P. Q. & van den Pol, A. N. Excitatory actions of GABA in developing rat hypothalamic neurones. The Journal of physiology 494 (Pt 2), 451-464 (1996); and Ben-Ari, Y. Excitatory actions of gaba during development: the nature of the nurture. Nature reviews. Neuroscience 3, 728-739 (2002).
The excitatory GABAergic transmission in the developing brain also explains why GABA agonists are often ineffective in controlling neonatal seizures, and sometimes can even exacerbate neonatal seizure activity. Farwell, J. R., et al. Phenobarbital for febrile seizures—effects on intelligence and on seizure recurrence. The New England journal of medicine 322, 364-369 (1990).
Classically, GABA excitatory versus inhibitory function has been attributed to the regulation by Cl−co-transporters NKCC1 and KCC2. 10. Kaila, K., Price, T. J., Payne, J. A., Puskarjov, M. & Voipio, J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nature reviews. Neuroscience 15, 637-654 (2014). Blaesse, P., Airaksinen, M. S., Rivera, C. & Kaila, K. Cation-chloride cotransporters and neuronal function. Neuron 61, 820-838 (2009). Previous study found that NKCC1 might facilitate neonatal seizures in rodent animals12, but recent clinical trial in infant babies found severe side effect of NKCC1 blocker bumetanide and very limited effect in treating neonatal seizure13. Dzhala, V. I., et al. NKCC1 transporter facilitates seizures in the developing brain. Nature medicine 11, 1205-1213 (2005); and Pressler, R. M., et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol 14, 469-477 (2015).
Unfortunately, to date there have been no effective drugs that can treat neonatal seizures successfully, prompting an urgent search of new drugs for neonatal epilepsy. What is needed in the art is a simple, effective and safe anti-epileptic drug to treat the unique characteristics of neonatal seizure.